Aminoacyl thiazolidides, aminoacyl pyrrolidides, N-dipeptididyl, O-acyl hydroxylamines and other compounds are known to act as inhibitors of the serum enzyme dipeptidyl peptidase IV (DP IV) and of analogous enzymes (see DEMUTH, H.-U., J. Enzyme Inhibition 3, 249 (1990); DEMUTH, H.-U., HEINS, J., in Dipeptidyl Peptidase IV (B. Fleischer, Ed.) R.G. Landes, Biomedical Publishers, Georgetown, 1995, 1-37).
It has been found that the T-cell-mediated immune response, for example in the case of transplantations, is influenced by means of stable inhibitors of dipeptidyl peptidase IV, (see KOROM, S., DEMEESTER, I., STADLBAUER, T.H.W., CHANDRAKER, A., SCHAUB, M., SAYEGH, M.H., BELYAEV, A., HAEMBRS, A., SCHARPE, S., KUPEC-WEGLINSKI, J.W., Inhibition of CD26/dipeptidyl peptidase IV activity in vivo prolongs cardiac allograft survival in rat recipients, Transplantation 63, 1495 (1997)). Rheumatoid arthritis can also be suppressed (see TANAKA, S., MURAKAMI, T., HORIKAWA, H., SUGIURA, M., KAWASHIMA, K., SUGITA, T., Suppression of arthritis by the inhibitors of dipeptidyl peptidase IV. Int. J. Immunopharmacol. 19, 15 (1997)).
It has also been found that, because of the associated temporary reduction in enzyme activity, administering stable inhibitors (effectors) of DP IV or of DP IV-analogous enzyme activity in the blood of a mammal causes reduced breakdown of the endogenous (or additionally exogenously administered) insulinotropic peptides gastric inhibitory polypeptides 1-42 (GIP1-42) and glucagon-like peptide amides-1 7-36 (GLP-17-36) (or GLP-17-37 or analogues thereof) by DP IV and DP IV-like enzymes and, accordingly, the drop in concentration of those peptide hormones or analogues thereof is reduced or delayed. The greater stability of the (endogenously present or exogenously introduced) incretins or analogues thereof, brought about by the action of the DP IV-effectors, which increases their availability for insulinotropic stimulation of the incretin receptors of the Langerhans cells in the pancreas, inter alia alters the effectiveness of the body's own insulin, resulting in stimulation of carbohydrate metabolism in the organism treated. As a result, the blood sugar level in the serum of the organism treated falls below the glucose concentration characteristic of hyperglycaemia. Consequently, by means of DP IV-inhibitors it is possible to prevent or alleviate metabolic anomalies, such as excess weight, glucosuria, hyperlipidaemia, and possible serious metabolic acidoses and diabetes mellitus, which are the result of prolonged elevated glucose concentrations in the blood (see DE 196 16 486).
By means of DP IV-inhibitors it is also possible, experimentally, to prevent the penetration of CD 26 (DP IV) positive cells by HIV (see WAKSELMAN, M., NGUYEN, C., MAZALEYRAT, J.-P., CALLEBAUT, C., KRUST, B., HOVANESSIAN, A.G., Inhibition of HIV-1 infection of CD 26+ but not CD26-cells by a potent cyclopeptidic inhibitor of the DPP IV activity of CD 26. Abstract P 44 of the 24th European Peptide Symposium 1996).
It has also been found that DP IV can modulate the activity of neuroactive peptides, such as neuropeptide Y and CLIP (see MENTLEIN, R., DAHMS, P., GRANDT, D., KRUGER, R., Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul. Pept. 49, 133 (1993); WETZL, W., WAGNER, T., VOGEL, D., DEMUTH, H.-U., BALSCHUN, D., Effects of the CLIP fragment ACTH 20-24 on the duration of REM sleep episodes. Neuropeptides, 31, 41 (1997)).
These varied actions of DP IV-inhibitors suggest that, when used in the case of a specific pathophysiological condition of a tissue, their actions can have an effect on other normal physiological states, for example in other organs. Those effects can have both positive and negative consequences for the target organism.
The problem of the present invention is accordingly to provide effectors of DP IV that have a high bioavailability of DP IV-inhibitors and a precisely defined duration of action in specific target tissues or target organs.
It was especially a problem of the present invention to provide inhibitors of DP IV that have a precisely defined short duration of action combined with high bio-availability.